WO2020070760A1 - An improved process for the preparation of 1,2,3-propanetriyl tris(4-phenylbutanoate) - Google Patents
An improved process for the preparation of 1,2,3-propanetriyl tris(4-phenylbutanoate)Info
- Publication number
- WO2020070760A1 WO2020070760A1 PCT/IN2019/050738 IN2019050738W WO2020070760A1 WO 2020070760 A1 WO2020070760 A1 WO 2020070760A1 IN 2019050738 W IN2019050738 W IN 2019050738W WO 2020070760 A1 WO2020070760 A1 WO 2020070760A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- formula
- solvent
- compound
- solvents
- phenylbutanoate
- Prior art date
Links
- ZSDBFLMJVAGKOU-UHFFFAOYSA-N O=C(CCCc1ccccc1)OCC(COC(CCCc1ccccc1)=O)OC(CCCc1ccccc1)=O Chemical compound O=C(CCCc1ccccc1)OCC(COC(CCCc1ccccc1)=O)OC(CCCc1ccccc1)=O ZSDBFLMJVAGKOU-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/08—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with the hydroxy or O-metal group of organic compounds
Definitions
- the present invention relates to an improved process for the preparation of 1,2,3- propanetriyl tris(4-phenylbutanoate) which is represented by the following structural formula- 1.
- the present invention relates to process of purification of 1 ,2,3- prop anetri y 1 tris(4-phenylbutanoate) compound of formula- 1.
- Glycerol phenylbutyrate which is a triglyceride containing 3 molecules of 4-phenylbutyric acid (PBA) linked to a glycerol backbone.
- Formula- 1 Glycerol phenylbutyrate was approved in US & Europe under the brand name of RAVICTI TM indicated for use as a nitrogen-binding agent for chronic management of adult and pediatric patients >2 years of age with urea cycle disorders (UCDs) that cannot be managed by dietary protein restriction and/or amino acid supplementation alone.
- UCDs urea cycle disorders
- IT 1317073 B l describes the preparation of glycerol phenylbutyrate by using 4- phenylbutyric acid and thionyl chloride in 5:1 ratio to give 4-phenylbutyryl chloride, followed treatment of the 4-phenylbutyryl chloride with a stoichiometric amount of glycerol.
- the said reported process is two step process and includes the usage of toxic environmental hazardous chemical thionyl chloride is not suitable for the large scale production.
- EP 2607366 Al describes the preparation of 4 -phenyl-butyric acid 2-hydroxy-3-(4- phenyl- butyryloxy)-propyl ester by reacting glycerol with 4-phenylbutyryl chloride.
- glycerol phenylbutyrate was obtained as by product.
- yield and purity of glycerol phenylbutyrate was very low, thus not suitable for large scale production.
- IN 3442/MUM/2013 describes the preparation of glycerol phenylbutyrate by reacting 4-phenylbutyryl chloride with glycerol in presence of organic base and dichloromethane solvent as a reaction medium, followed by isolating the glycerol phenylbutyrate by chromatographic technique.
- glycerol phenylbutyrate was purified of by cumbersome and tedious flash column chromatography. This requires extra man hours, resource and excess of solvents this leads to the generation of lot of spent and unwanted waste products which are difficult to dispose and causes pollution of the environment. This makes the above said process uneconomical and not suitable for large scale production.
- the present inventors have developed an improved industrially viable economic process for the preparation of glycerol phenylbutyrate of compound of formula- 1 by overcoming the above said drawbacks providing with high yields and purity.
- Glycerol phenylbutyrate is a clear, colourless to pale yellow liquid. Purification of oil is difficult. All the prior art literature discloses the purification of Glycerol phenylbutyrate compound of formula- 1 using silicagel column chromatography which is highly time consumable process requires extra man hours, resource and excess of solvents in plant scale level. The present inventors developed an improved industrially viable economic process for the purification of Glycerol phenylbutyrate compound of formula- 1 by avoiding column chromatography.
- the first embodiment of the present invention is to provide an improved process for the preparation of l,2,3-propanetriyl tris(4-phenylbutanoate) compound of formula- 1.
- the second embodiment of the present invention is to provide a process for the purification of l,2,3-propanetriyl tris(4-phenylbutanoate) compound of formula- 1.
- the third embodiment of the present invention is to provide another process for the purification of l,2,3-propanetriyl tris(4-phenylbutanoate) compound of formula- 1.
- the present invention is simple and carried out in single step with shorter reaction hours and provided the desired compound with high yield.
- the present invention provides an improved process for the preparation of 1 ,2,3- prop anetri y 1 tris(4-phenylbutanoate) compound of formula- 1.
- solvent used in the present invention refers to “hydrocarbon solvents” such as n-hexane, n-heptane, cyclohexane, pet ether, benzene, toluene, pentane, cycloheptane, methyl cyclohexane, ethylbenzene, m-, o-, or p-xylene, or naphthalene and the like;“ether solvents” such as dimethoxymethane, tetrahydrofuran, l,3-dioxane, l,4-dioxane, furan, diethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dimethyl ether, anisole, t-butyl methyl ether, l,2-dimethoxy
- the term“base” refers to inorganic bases like “alkali metal carbonates” such as sodium carbonate, potassium carbonate, lithium carbonate and the like;“alkali metal bicarbonates” such as sodium bicarbonate, potassium bicarbonate and the like;“alkali metal hydroxides” such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like; “alkali metal alkoxides” such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tert.butoxide, potassium tert.butoxide, lithium tert.butoxide and the like; alkali metal hydrides such as sodium hydride, potassium hydride, lithium hydride and the like; alkali metal amides such as sodium amide, potassium amide, lithium amide and the like; and organic bases like dimethylamine, diethylamine, diisopropyl amine, diisopropylethylamine, diiso
- the first embodiment of the present invention provides an improved process for the preparation of l,2,3-propanetriyl tris(4-phenylbutanoate) compound of formula- 1, comprises reacting 4-phenylbutyric acid compound of formula-2 with glycerol to provide a compound of formula- 1.
- An aspect of the first embodiment involves reacting compound of formula-2 with glycerol, optionally in presence of a coupling agent, optionally in a solvent and optionally in presence of a base to provide l,2,3-propanetriyl tris(4-phenylbutanoate) compound of formula- 1.
- solvent is selected from alcohol solvents, chloro solvents, ester solvents, ether solvents, ketone solvents, nitrile solvents, hydrocarbon solvents, polar aprotic solvents, polar solvents, water and mixtures thereof;
- the base is selected from organic or inorganic bases;
- the coupling agent is selected from N,N'-dicyclohexylcarbodiimide (DCC), N,N’- diisopropylcarbodiimide (DIC), carbonyldiimidazole (CDI), l-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride (EDC.HC1), 0-(7-aza-benzotriazole-l- yl)-N,N,N',N'-tetramethyl uronium hexafluoro phosphate (HATU), alkyl or aryl chloroformates such as ethyl chloroformate, benzyl
- the second embodiment of the present invention provides purification of 1 ,2,3- prop anetri y 1 tris(4-phenylbutanoate) compound of formula- 1 comprises:
- the solvent in step (a) is selected from alcohol solvents, water and mixtures thereof; isolating the compound of formula- 1 in step-b) from a mixture obtained in step-a) by the removal of solvent by known techniques which are selected from but not limited to by evaporation, evaporation under reduced pressure, flash evaporation, vacuum drying, concentrating the reaction mixture, distillation optionally under reduced pressure, by decanting, by separating the layers or any other suitable techniques which may be used for the removal of solvent.
- step-a) wherein the process further comprises combining the mixture obtained in step-a) with another solvent followed by distilling the said solvent from the resulting mixture to obtain pure compound of formula- 1.
- Another solvent is same or different from the solvent used in one or more above embodiment, selected from chloro solvents, ester solvents, ether solvents, ketone solvents, nitrile solvents, hydrocarbon solvents, protic solvents, polar aprotic solvents, and mixtures thereof.
- a process for the purification of l,2,3-Propanetriyl tris(4-phenylbutanoate) compound of formula- 1 comprises:
- step-a) combining the compound of formula- 1 with a solvent comprises isopropanol, b) separating the layers obtained in step-a),
- optionally further purifying the compound of formula- 1 by dissolving the compound of formula- 1 in another suitable solvent, treating the solution with charcoal or any other suitable material, filtering the solution to make it particle free and removing the solvent from the solution to get pure compound of formula- 1.
- Another solvent is same or different from the solvent used in one or more above embodiment, selected from chloro solvents, ester solvents, ether solvents, ketone solvents, nitrile solvents, hydrocarbon solvents, protic solvents, polar aprotic solvents, and mixtures thereof.
- suitable techniques which may be used for the removal of solvent from the solution includes but not limited to evaporation, evaporation under reduced pressure, flash evaporation, vacuum drying, concentrating the reaction mixture, distillation optionally under reduced pressure, by decanting, by separating the layers or by any other suitable techniques known in the art.
- the solvent may be removed optionally under reduced pressures, at temperatures less than about l30°C, less than about 60°C, less than about 40°C, less than about 20°C, less than about 0°C, less than about -20°C, less than about -40°C or less than about - 60°C.
- the third embodiment of the present invention provides a process for the purification of l,2,3-propanetriyl tris(4-phenylbutanoate) compound of formula- 1 comprises:
- isolating substantially pure compound of formula- 1 is by extracting the compound adsorbed on silica into a solvent followed by removing the said solvent;
- the solvent is selected from hydrocarbon solvents, ester solvents, chloro solvents and mixtures thereof; preferably mixture of hydrocarbon and ester solvent; more preferably mixture of cyclohexane and ethyl acetate; the removal of solvent from the solution but not limited to evaporation, evaporation under reduced pressure, flash evaporation, vacuum drying, concentrating the reaction mixture, distillation optionally under reduced pressure, by decanting, by separating the layers or by any other suitable techniques known in the art.
- the solvent may be removed optionally under reduced pressures, at temperatures less than about l30°C, less than about 60°C, less than about 40°C, less than about 20°C, less than about 0°C, less than about -20°C, less than about -40°C or less than about - 60°C.
- isolating substantially pure compound of formula- 1 comprises:
- step-a) extracting the compound of formula- 1 adsorbed on silica into a first solvent, b) treating the mixture obtained in step-a) with an aqueous basic solution,
- step-b) d) combining the compound obtained in step-b) or step-c) with a second solvent, e) isolating substantially pure compound of formula- 1.
- isolating substantially pure compound of formula- 1 from a mixture obtained in step-d) is by distilling the solvent optionally under reduced pressure, or by decanting the solvent;
- the first solvent is selected from hydrocarbon solvents, ester solvents, chloro solvents, and mixtures thereof;
- the aqueous basic solution in step-b) is prepared by dissolving inorganic base in water;
- the second solvent is selected from alcohol solvents, water optionally combining with hydrocarbon solvents, and ester solvents.
- “Substantially pure” or“Pure” means compound of formula- 1 prepared by the process of the present invention is substantially free from the impurities.
- the compound of formula- 1 obtained according to the present invention is substantially pure having a purity >95% by HPLC, preferably >97% by HPLC, more preferably >99% by HPLC.
- a liquid chromatograph is equipped with variable wavelength UV Detector.
- Substantially pure compound of formula- 1 of the present invention prepared by the processes as illustrated in the present invention is useful for the preparation of various pharmaceutical compositions formulated in a manner suitable for the route of administration to be used.
- 4-phenylbutyric acid compound of formula-2 which is used in the present invention is commercially available in the market (or) it can be prepared by any of the known prior art processes.
- Substantially pure compound of formula- 1 of the present invention is useful and well suitable for the preparation of various pharmaceutical compositions formulated in a manner suitable for the route of administration to be used where at least a portion of compound of formula- 1 is present in the composition.
- Such pharmaceutical compositions may comprise compound of formula- 1 present in the composition in a range of between 0.005% and 100% (wt/wt), with the balance of the pharmaceutical composition comprises additional substances such as excipients, diluents, lubricants, binders, wetting agents, disintegrating agents, glidants, sweetening agents, flavoring agents, emulsifying agents, solubilizing agents, pH buffering agents, perfuming agents, surface stabilizing agents, suspending agents and other conventional pharmaceutically inactive agents.
- a pharmaceutical composition comprises substantially pure compound of formula- 1 and one or more pharmaceutically acceptable carriers for use as a nitrogen-binding agent for chronic management of adult and pediatric patients >2 years of age with urea cycle disorders (UCDs) that cannot be managed by dietary protein restriction and/or amino acid supplementation alone.
- UCDs urea cycle disorders
- Example-1 Preparation of the compound of formula-1.
- Example-2 Purification of compound of formula-1.
- Example-3 Preparation of the compound of formula-1.
- Thionyl chloride (57.7 g) was added to the mixture of cyclohexane (500 ml), dimethylformamide (2 ml) and compound of formula-2 (100 g) at 25 to 30°C and stirred for 2 hours at the same temperature. Distilled off the solvent from the reaction mixture. Toluene (200 ml) was added to the reaction mixture at 25 to 30°C and stirred for 10 min at the same temperature. Above mixture was slowly added to the mixture of glycerol (16 g) and N-methylimidazole (71.3 g) in toluene (300 ml) at 25 to 30°C and stirred for 2 hours at the same temperature. Water was added to reaction mixture. Layers were separated.
- Example-4 Preparation of compound of formula-1.
- Glycerol 25 g was added to the mixture of cyclohexane (470 ml) and compound of formula-2 (156 g) at 25 to 30°C. Cooled the mixture to 15 to 20°C. 4- Dimethylaminopyridine (13.26 g) followed by a solution of dicyclohexylcarbodiimide (207.24 g) in cyclohexane (1090 ml) were slowly added to the above mixture and stirred the reaction mixture for 5 hours at the same temperature. Water was added to reaction mixture at 15 to 20°C and stirred the reaction mixture for 45 minutes at same temperature. Filtered the reaction mixture through high-flow bed and washed with cyclohexane.
- Example-5 Purification of compound of formula-1.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention relates to an improved process for the preparation of 1,2,3-Propanetriyl tris (4-phenylbutanoate) compound of formula-1, comprising 4-phenyl butyric acid compound of formula-2 with glycerol to provide 1,2,3-Propanetriyl tris (4-phenylbutanoate) compound of formula-1. Further, the present invention relates to process for the purification of 1,2,3-Propanetriyl tris (4-phenyl butanoate) compound of formula-1.
Description
An improved process for the preparation of 1,2,3-Propanetriyl tris(4- phenylbutanoate)
Related application:
This application claims priority to Indian patent application number 201841037577 filed on October 04, 2018 which are incorporated herein by reference in its entirety.
Field of the invention:
The present invention relates to an improved process for the preparation of 1,2,3- propanetriyl tris(4-phenylbutanoate) which is represented by the following structural formula- 1.
Formula- 1
Further, the present invention relates to process of purification of 1 ,2,3- prop anetri y 1 tris(4-phenylbutanoate) compound of formula- 1.
Background of the invention:
l,2,3-Propanetriyl tris(4-phenylbutanoate) is commonly known as Glycerol phenylbutyrate which is a triglyceride containing 3 molecules of 4-phenylbutyric acid (PBA) linked to a glycerol backbone.
Formula- 1
Glycerol phenylbutyrate was approved in US & Europe under the brand name of RAVICTI™ indicated for use as a nitrogen-binding agent for chronic management of adult and pediatric patients >2 years of age with urea cycle disorders (UCDs) that cannot be managed by dietary protein restriction and/or amino acid supplementation alone.
l,2,3-Propanetriyl tris(4-phenylbutanoate) was first described in US 5968979 A. This patent also discloses preparation of the compounds of the invention by standard esterification procedures. US’979 did not disclose specific process for the preparation of l,2,3-propanetriyl tris(4-phenylbutanoate).
IT 1317073 B l describes the preparation of glycerol phenylbutyrate by using 4- phenylbutyric acid and thionyl chloride in 5:1 ratio to give 4-phenylbutyryl chloride, followed treatment of the 4-phenylbutyryl chloride with a stoichiometric amount of glycerol. The said reported process is two step process and includes the usage of toxic environmental hazardous chemical thionyl chloride is not suitable for the large scale production.
Drug Metabolism and Disposition, 2004, 32 (1), 10-19 describes the preparation of glycerol phenylbutyrate by reacting glycerol with excess 4-phenylbutyryl chloride in the presence of pyridine and catalytic amounts of N,N- dimethylaminopyridine further the product was purified by flash column chromatography on silica. In the above process glycerol phenylbutyrate was purified by cumbersome and tedious flash column chromatography. This requires extra man hours, resource and excess of solvents this leads to the generation of lot of spent and unwanted waste products which are difficult to dispose and causes pollution of the environment. This makes the above said process uneconomical and not suitable for large scale production.
Journal of Biotechnology, 2007, 127(4), 694-702 describes the preparation of glycerol phenylbutyrate from glycerol and 4-phenylbutyric acid by lipase-catalyzed esterification in a solvent-free system. The above said process includes the usage of lipase enzyme.
EP 2607366 Al describes the preparation of 4 -phenyl-butyric acid 2-hydroxy-3-(4- phenyl- butyryloxy)-propyl ester by reacting glycerol with 4-phenylbutyryl chloride. In this preparation glycerol phenylbutyrate was obtained as by product. In this process yield and purity of glycerol phenylbutyrate was very low, thus not suitable for large scale production.
IN 3442/MUM/2013 describes the preparation of glycerol phenylbutyrate by
reacting 4-phenylbutyryl chloride with glycerol in presence of organic base and dichloromethane solvent as a reaction medium, followed by isolating the glycerol phenylbutyrate by chromatographic technique. In the above process glycerol phenylbutyrate was purified of by cumbersome and tedious flash column chromatography. This requires extra man hours, resource and excess of solvents this leads to the generation of lot of spent and unwanted waste products which are difficult to dispose and causes pollution of the environment. This makes the above said process uneconomical and not suitable for large scale production.
The prior art processes suffer from disadvantages including formation of impurities, low product quality, use of hazardous, toxic reagents, multiple step processes. These disadvantages make the process expensive and industrially unviable. Thus, there remains a need to develop an improved process for the preparation glycerol phenylbutyrate, which is simple, economic and industrially viable process with high yield and purity.
The present inventors have developed an improved industrially viable economic process for the preparation of glycerol phenylbutyrate of compound of formula- 1 by overcoming the above said drawbacks providing with high yields and purity.
Glycerol phenylbutyrate is a clear, colourless to pale yellow liquid. Purification of oil is difficult. All the prior art literature discloses the purification of Glycerol phenylbutyrate compound of formula- 1 using silicagel column chromatography which is highly time consumable process requires extra man hours, resource and excess of solvents in plant scale level. The present inventors developed an improved industrially viable economic process for the purification of Glycerol phenylbutyrate compound of formula- 1 by avoiding column chromatography.
Brief description of the invention:
The first embodiment of the present invention is to provide an improved process for the preparation of l,2,3-propanetriyl tris(4-phenylbutanoate) compound of formula- 1.
The second embodiment of the present invention is to provide a process for the purification of l,2,3-propanetriyl tris(4-phenylbutanoate) compound of formula- 1.
The third embodiment of the present invention is to provide another process for the purification of l,2,3-propanetriyl tris(4-phenylbutanoate) compound of formula- 1.
Advantages of the present invention:
• Usage of commercially available and cheaper reagent and solvent like cyclohexane and ethyl acetate.
• Provides eco-friendly and cost-effective process
• Avoids the usage of cumbersome and tedious column chromatography.
• The present invention is simple and carried out in single step with shorter reaction hours and provided the desired compound with high yield.
Detailed description of the invention:
The present invention provides an improved process for the preparation of 1 ,2,3- prop anetri y 1 tris(4-phenylbutanoate) compound of formula- 1.
As used herein the term “solvent” used in the present invention refers to “hydrocarbon solvents” such as n-hexane, n-heptane, cyclohexane, pet ether, benzene, toluene, pentane, cycloheptane, methyl cyclohexane, ethylbenzene, m-, o-, or p-xylene, or naphthalene and the like;“ether solvents” such as dimethoxymethane, tetrahydrofuran, l,3-dioxane, l,4-dioxane, furan, diethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dimethyl ether, anisole, t-butyl methyl ether, l,2-dimethoxy ethane and the like;“ester solvents” such as methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate and the like; “polar-aprotic solvents such as dimethylacetamide (DMA), dimethylformamide (DMF), dimethylsulfoxide (DMSO), N-methylpyrrolidone (NMP) and the like;“chloro solvents” such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride and the like;“ketone solvents” such as acetone, methyl ethyl ketone, methyl isobutylketone and the like;“nitrile solvents” such as acetonitrile, propionitrile, isobutyronitrile and the like;“alcohol solvents” such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2- trifluoroethanol, ethylene glycol, 1, 2-propanediol (propylene glycol), 2-methoxyethanol, 1, 2-ethoxyethanol, diethylene glycol, 1, 2, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, or glycerol and the like;“polar solvents” such as water or mixtures thereof.
As used herein the present invention the term“base” refers to inorganic bases like “alkali metal carbonates” such as sodium carbonate, potassium carbonate, lithium carbonate and the like;“alkali metal bicarbonates” such as sodium bicarbonate, potassium
bicarbonate and the like;“alkali metal hydroxides” such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like; “alkali metal alkoxides” such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tert.butoxide, potassium tert.butoxide, lithium tert.butoxide and the like; alkali metal hydrides such as sodium hydride, potassium hydride, lithium hydride and the like; alkali metal amides such as sodium amide, potassium amide, lithium amide and the like; and organic bases like dimethylamine, diethylamine, diisopropyl amine, diisopropylethylamine, diisobutylamine, triethylamine, tertiary butyl amine, benzyl amine, pyridine, 4-dimethylaminopyridine (DMAP), N-methyl morpholine (NMM), 2,6- lutidine, lithium diisoprop ylamide; organosilicon bases such as lithium hexamethyldisilazide (LiHMDS), sodium hexamethyldisilazide (NaHMDS), potassium hexamethyldisilazide (KHMDS) or mixtures thereof.
The first embodiment of the present invention provides an improved process for the preparation of l,2,3-propanetriyl tris(4-phenylbutanoate) compound of formula- 1, comprises reacting 4-phenylbutyric acid compound of formula-2 with glycerol to provide a compound of formula- 1.
An aspect of the first embodiment involves reacting compound of formula-2 with glycerol, optionally in presence of a coupling agent, optionally in a solvent and optionally in presence of a base to provide l,2,3-propanetriyl tris(4-phenylbutanoate) compound of formula- 1.
“Solvent” is selected from alcohol solvents, chloro solvents, ester solvents, ether solvents, ketone solvents, nitrile solvents, hydrocarbon solvents, polar aprotic solvents, polar solvents, water and mixtures thereof; the base is selected from organic or inorganic bases; the coupling agent is selected from N,N'-dicyclohexylcarbodiimide (DCC), N,N’- diisopropylcarbodiimide (DIC), carbonyldiimidazole (CDI), l-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride (EDC.HC1), 0-(7-aza-benzotriazole-l- yl)-N,N,N',N'-tetramethyl uronium hexafluoro phosphate (HATU), alkyl or aryl chloroformates such as ethyl chloroformate, benzylchloroformate, diphenylphosphoroazidate (DPPA), thionyl chloride, pivalyl chloride, oxalyl chloride, phosphorous oxychloride, phosphorous pentachloride, 4-methyl-2-oxopentanoyl chloride (i-BuCOCOCl), benzotriazol-l-yl-oxytripyrrolidino phosphonium hexafluorophosphate (PyBOP), methane sulfonyl chloride and the like; optionally in combination with 1-
hydroxy-7-azatriazole (HOAt), l-hydroxybenzotriazole (HOBt), 1 -hydroxy- 1H- 1,2, 3- triazole-4-carboxylate (HOCt), 0-(benzotriazol-l-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU), N-hydroxysuccinamide (HOSu), N-hydroxysulfosuccinimide (Sulfo-NHS), 4-dimethylaminopyridine (DMAP).
The above process of the present invention is schematically represented as follows:
The second embodiment of the present invention provides purification of 1 ,2,3- prop anetri y 1 tris(4-phenylbutanoate) compound of formula- 1 comprises:
a) washing compound of formula- 1 with a solvent,
b) isolating pure compound of formula- 1.
Wherein the solvent in step (a) is selected from alcohol solvents, water and mixtures thereof; isolating the compound of formula- 1 in step-b) from a mixture obtained in step-a) by the removal of solvent by known techniques which are selected from but not limited to by evaporation, evaporation under reduced pressure, flash evaporation, vacuum drying, concentrating the reaction mixture, distillation optionally under reduced pressure, by decanting, by separating the layers or any other suitable techniques which may be used for the removal of solvent.
In the first aspect of the second embodiment, wherein the process further comprises combining the mixture obtained in step-a) with another solvent followed by distilling the said solvent from the resulting mixture to obtain pure compound of formula- 1.
Another solvent is same or different from the solvent used in one or more above embodiment, selected from chloro solvents, ester solvents, ether solvents, ketone solvents, nitrile solvents, hydrocarbon solvents, protic solvents, polar aprotic solvents, and mixtures thereof.
In the second aspect of the second embodiment, a process for the purification of
l,2,3-Propanetriyl tris(4-phenylbutanoate) compound of formula- 1 comprises:
a) combining the compound of formula- 1 with a solvent comprises isopropanol, b) separating the layers obtained in step-a),
c) adding cyclohexane to the product layer obtained in step-b),
d) distilling off the solvent to get substantially pure compound of formula- 1.
In third aspect of the second embodiment, optionally further purifying the compound of formula- 1 by dissolving the compound of formula- 1 in another suitable solvent, treating the solution with charcoal or any other suitable material, filtering the solution to make it particle free and removing the solvent from the solution to get pure compound of formula- 1.
Another solvent is same or different from the solvent used in one or more above embodiment, selected from chloro solvents, ester solvents, ether solvents, ketone solvents, nitrile solvents, hydrocarbon solvents, protic solvents, polar aprotic solvents, and mixtures thereof.
In the above process, suitable techniques which may be used for the removal of solvent from the solution includes but not limited to evaporation, evaporation under reduced pressure, flash evaporation, vacuum drying, concentrating the reaction mixture, distillation optionally under reduced pressure, by decanting, by separating the layers or by any other suitable techniques known in the art.
The solvent may be removed optionally under reduced pressures, at temperatures less than about l30°C, less than about 60°C, less than about 40°C, less than about 20°C, less than about 0°C, less than about -20°C, less than about -40°C or less than about - 60°C.
The third embodiment of the present invention provides a process for the purification of l,2,3-propanetriyl tris(4-phenylbutanoate) compound of formula- 1 comprises:
a) adsorbing the compound of formula- 1 on silica,
b) isolating substantially pure compound of formula- 1
In first aspect of the third embodiment, wherein isolating substantially pure compound of formula- 1 is by extracting the compound adsorbed on silica into a solvent followed by removing the said solvent; the solvent is selected from hydrocarbon solvents,
ester solvents, chloro solvents and mixtures thereof; preferably mixture of hydrocarbon and ester solvent; more preferably mixture of cyclohexane and ethyl acetate; the removal of solvent from the solution but not limited to evaporation, evaporation under reduced pressure, flash evaporation, vacuum drying, concentrating the reaction mixture, distillation optionally under reduced pressure, by decanting, by separating the layers or by any other suitable techniques known in the art.
The solvent may be removed optionally under reduced pressures, at temperatures less than about l30°C, less than about 60°C, less than about 40°C, less than about 20°C, less than about 0°C, less than about -20°C, less than about -40°C or less than about - 60°C.
In second aspect of the third embodiment, wherein isolating substantially pure compound of formula- 1 comprises:
a) extracting the compound of formula- 1 adsorbed on silica into a first solvent, b) treating the mixture obtained in step-a) with an aqueous basic solution,
c) optionally removing the solvent from the organic layer,
d) combining the compound obtained in step-b) or step-c) with a second solvent, e) isolating substantially pure compound of formula- 1.
Wherein isolating substantially pure compound of formula- 1 from a mixture obtained in step-d) is by distilling the solvent optionally under reduced pressure, or by decanting the solvent; the first solvent is selected from hydrocarbon solvents, ester solvents, chloro solvents, and mixtures thereof; the aqueous basic solution in step-b) is prepared by dissolving inorganic base in water; the second solvent is selected from alcohol solvents, water optionally combining with hydrocarbon solvents, and ester solvents.
"Substantially pure" or“Pure” means compound of formula- 1 prepared by the process of the present invention is substantially free from the impurities. The compound of formula- 1 obtained according to the present invention is substantially pure having a purity >95% by HPLC, preferably >97% by HPLC, more preferably >99% by HPLC.
The following impurities are observed during the synthesis of the compound of formula- 1 as per the present invention. Along with these impurities, the starting materials
are well controlled as per ICH guide lines in the compound of formula- 1.
HPLC Method of Analysis:
l,2,3-Propanetriyl tris(4-phenylbutanoate) and its related substances were analysed by HPLC with the following chromatographic conditions:
Apparatus: A liquid chromatograph is equipped with variable wavelength UV Detector. Column: Inertsil ODS-2 150 X 4.6 mm, 5.0 pm; Wavelength: 210 nm; Column temperature: 25°C; Injection volume: 10 pL; Elution: Gradient; Diluent: Acetonitrile: water (70:30) v/v; Needle wash: 2% NaOH solution in water.
Buffer Preparation:
i) Accurately transfer 1000 ml of milli-Q water into a suitable cleaned and dry beaker. ii) Transfer 1.0 ml orthophosphoric acid into 1000 ml of milli-Q-water and mix well and filter the obtained solution through 0.22 pm PVDF membrane
Mobile phase-A: Buffer 100%; Mobile phase-B: Acetonitrile: Water (90:10) v/v.
Substantially pure compound of formula- 1 of the present invention prepared by the processes as illustrated in the present invention is useful for the preparation of various pharmaceutical compositions formulated in a manner suitable for the route of administration to be used.
4-phenylbutyric acid compound of formula-2 which is used in the present invention is commercially available in the market (or) it can be prepared by any of the known prior art processes.
Substantially pure compound of formula- 1 of the present invention is useful and well suitable for the preparation of various pharmaceutical compositions formulated in a manner suitable for the route of administration to be used where at least a portion of compound of formula- 1 is present in the composition. Such pharmaceutical compositions may comprise compound of formula- 1 present in the composition in a range of between 0.005% and 100% (wt/wt), with the balance of the pharmaceutical composition comprises additional substances such as excipients, diluents, lubricants, binders, wetting agents, disintegrating agents, glidants, sweetening agents, flavoring agents, emulsifying agents, solubilizing agents, pH buffering agents, perfuming agents, surface stabilizing agents, suspending agents and other conventional pharmaceutically inactive agents.
In an aspect of the present invention provides a pharmaceutical composition comprises substantially pure compound of formula- 1 and one or more pharmaceutically acceptable carriers for use as a nitrogen-binding agent for chronic management of adult and pediatric patients >2 years of age with urea cycle disorders (UCDs) that cannot be managed by dietary protein restriction and/or amino acid supplementation alone.
The best mode of carrying out the present invention was illustrated by the below mentioned examples. These examples provided as illustration only and hence should not be construed as limitation of the scope of the invention.
Examples:
Example-1: Preparation of the compound of formula-1.
The solution of dicyclohexylcarbodiimide (207 g) in dichloromethane (937 ml) was slowly added to a mixture of compound of formula-2 (156 g), dichloromethane (300 ml),
glycerol (25 g) and 4-Dimethylaminopyridine (13.26 g) at 25 to 30°C and stirred the reaction mixture for 3 hours at the same temperature. Cooled the reaction mixture to 0 to 5°C and stirred for 2 hours at the same temperature. Filtered the reaction mixture through high-flow bed and washed with dichlorome thane. The organic layer was washed with aqueous sodium bicarbonate solution followed by with water and finally with aqueous sodium chloride solution. Distilled off the solvent completely from the organic layer under reduced pressure to get the title compound. Yield: 140 g.
Example-2: Purification of compound of formula-1.
Compound of formula- 1 (25 g) was added to the isopropanol (25 ml) at 25 to 30°C and stirred for 10 minutes at the same temperature. Separated the layers. Further washing the compound layer/bottom layer with isopropanol at 25 to 30°C. Layers were separated. To the bottom layer, cyclohexane and charcoal were added at 25 to 30°C and stirred for 10 minutes at the same temperature. Filtered the mixture through hyflow bed, washed with cyclohexane and distilled off the solvent completely to get the pure compound.
Yield: 12 g. Purity: 99.89% by HPLC.
Example-3: Preparation of the compound of formula-1.
Thionyl chloride (57.7 g) was added to the mixture of cyclohexane (500 ml), dimethylformamide (2 ml) and compound of formula-2 (100 g) at 25 to 30°C and stirred for 2 hours at the same temperature. Distilled off the solvent from the reaction mixture. Toluene (200 ml) was added to the reaction mixture at 25 to 30°C and stirred for 10 min at the same temperature. Above mixture was slowly added to the mixture of glycerol (16 g) and N-methylimidazole (71.3 g) in toluene (300 ml) at 25 to 30°C and stirred for 2 hours at the same temperature. Water was added to reaction mixture. Layers were separated. The aqueous layer was extracted with toluene. Combined the organic layers. The organic layer was washed with aqueous sodium bicarbonate solution followed by with aqueous sodium chloride solution. Distilled off the solvent completely from the organic layer under reduced pressure to get the title compound. Yield: 90 g.
Example-4: Preparation of compound of formula-1.
Glycerol (25 g) was added to the mixture of cyclohexane (470 ml) and compound of formula-2 (156 g) at 25 to 30°C. Cooled the mixture to 15 to 20°C. 4- Dimethylaminopyridine (13.26 g) followed by a solution of dicyclohexylcarbodiimide (207.24 g) in cyclohexane (1090 ml) were slowly added to the above mixture and stirred the reaction mixture for 5 hours at the same temperature. Water was added to reaction
mixture at 15 to 20°C and stirred the reaction mixture for 45 minutes at same temperature. Filtered the reaction mixture through high-flow bed and washed with cyclohexane. The above obtained filtrate was washed with aqueous acetic acid solution. The organic layer was washed with aqueous sodium carbonate solution and followed by with water. To the organic layer charcoal was added at 25 to 30°C, cooled the mixture to l0-l5°C and stirred for 2 hours at the same temperature. Filtered the mixture through hyflow, washed with cyclohexane and distilled off the solvent completely from the filtrate to get the title compound. Yield: 134 g. Purity: 96.06% by HPLC.
Example-5: Purification of compound of formula-1.
Compound of formula- 1 (250 g) was added to cyclohexane (750 ml) at 25 to 30°C and cooled the mixture to 10 to 15 °C. Silica (500 gm) was added the above mixture at 10 to l5°C and stirred for 15 minutes at the same temperature. Distilled off the solvent completely from the above mixture. Extracted the compound into the mixture of cyclohexane and ethyl acetate from the above obtained mixture at 30 to 35°C. Combined the extracted layers and washed with aqueous sodium carbonate solution and with water followed by with aqueous sodium chloride solution. Distilled off the solvent completely from the organic layer. The mixture of cyclohexane and isopropanol was added to the above obtained residue at 30 to 35°C and stirred for 15 minutes at the same temperature. Separated the top and bottom layers. To the bottom layer, mixture of cyclohexane and isopropanol was added at 30 to 35°C and stirred for 15 minutes at the same temperature. Separated the top and bottom layers. Repeated the same process for several times. Combined the bottom layers, cyclohexane (1000 ml) was added to it, filtered through high-flow bed and washed with cyclohexane. Distilled off the solvent completely from filtrate to get the pure compound.
Yield: 70 g, Purity: 99.90% by HPLC; Monomer impurity: Not detected; Dimer impurity: Not detected.
Claims
1. A process for the preparation of l,2,3-propanetriyl tris(4-phenylbutanoate) compound of formula- 1
Formula- 1
comprises:
a) reacting compound of formula-2
Formula-2
with glycerol in presence of a coupling agent and a base in a solvent to obtain 1 ,2,3- prop ane tri yl tris(4-phenylbutanoate) compound of formula- 1 ,
b) optionally purifying the compound of formula- 1 obtained in step-a).
2. The process of claim 1, wherein the solvent is selected from chloro solvents, ester solvents, ether solvents, nitrile solvents, hydrocarbon solvents, polar aprotic solvents, and mixtures thereof.
3. The process of claim 1, wherein the base is selected from organic bases or inorganic bases.
4. The process of claim 1, wherein the coupling agent is selected from N,N'- di cyclohexyl carbodiimide (DCC), N,N’-diisopropylcarbodiimide (DIC), carbonyldiimidazole (CDI), l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC.HC1), 0-(7-aza- benzotriazole-l-yl)-N,N,N',N'-tetramethyl uronium hexafluoro phosphate (HATU), alkyl or aryl chloroformates such as ethyl chloroformate, benzylchloroformate,
diphenylphosphoroazidate (DPP A), benzotriazol-l-yl-oxytripyrrolidino phosphonium hexafluorophosphate (PyBOP), methane sulfonyl chloride; optionally in combination with 1- hydroxy-7-azatriazole (HOAt), 1 -hydroxybenzotriazole (HOBt), l-hydroxy-lH-l,2,3- triazole-4-carboxylate (HOCt), 0-(benzotriazol-l-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU), N-hydroxysuccinamide (HOSu), N-hydroxysulfosuccinimide (Sulfo-NHS), and 4-dimethylaminopyridine (DMAP).
5. A process for the purification of l,2,3-propanetriyl tris(4-phenylbutanoate) compound of formula- 1 comprises:
a) adsorbing the compound of formula- 1 on silica,
b) isolating substantially pure compound of formula- 1.
6. The process of claim 5, wherein isolating substantially pure compound of formula- 1 is by extracting the compound adsorbed on silica into a solvent followed by removing the said solvent.
7. The process of claim 6, wherein the solvent is selected from hydrocarbon solvents, ester solvents, chloro solvents and mixtures thereof.
8. The process of claim 7, wherein the solvent is a mixture of hydrocarbon and ester.
9. The process of claim 5, wherein isolating substantially pure compound of formula- 1 comprises:
a) extracting the compound of formula- 1 adsorbed on silica into a first solvent,
b) treating the mixture obtained in step-a) with an aqueous basic solution,
c) optionally removing the solvent from the organic layer,
d) combining the compound obtained in step-b) or step-c) with a second solvent, e) isolating substantially pure compound of formula- 1.
10. The process of claim 9, wherein isolating substantially pure compound of formula- 1 from a mixture obtained in step-d) is by distilling the solvent optionally under reduced pressure, or by decanting the solvent.
11. The process of claim 9, wherein the first solvent is selected from hydrocarbon solvents, ester solvents, chloro solvents, and mixtures thereof.
12. The process of claim 9, wherein the aqueous basic solution in step-b) is prepared by dissolving inorganic base in water.
13. The process of claim 9, wherein the second solvent is selected from alcohol solvents, water optionally combining with hydrocarbon solvents, and ester solvents.
14. A process for the purification of l,2,3-propanetriyl tris(4-phenylbutanoate) compound of formula- 1 comprises:
a) washing the compound of formula- 1 with a solvent,
b) isolating substantially pure compound of formula- 1.
15. A process of claim 14, wherein the solvent is selected from alcohol solvents, water, and mixtures thereof.
16. A process of claim 14, wherein isolating substantially pure compound of formula-l from a mixture obtained in step-a) is by distilling the solvent optionally under reduced pressure, or by decanting the solvent.
17. A process of claim 14, wherein the process further comprises combining the mixture obtained in step-a) with a solvent followed by distilling the solvent from the resulting mixture to obtain pure compound of formula- 1.
18. A process of claim 17, wherein the solvent is selected from hydrocarbon solvents, chloro solvents, ester solvents, and mixtures thereof.
19. A process for the purification of l,2,3-propanetriyl tris(4-phenylbutanoate) compound of formula- 1 comprises:
a) combining the compound of formula- 1 with a solvent comprises isopropanol,
b) separating the layers obtained in step-a),
c) adding cyclohexane to the bottom layer obtained in step-b),
d) distilling off the solvent to get substantially pure compound of formula- 1.
20. The compound of formula- 1 obtained according to any of preceding claims having a purity of greater than about 95% by HPLC.
21. The compound of formula- 1 obtained according to any of preceding claims having less than about 0.05% of monomer impurity by HPLC, and/or less than about 0.05% of dimer impurity by HPLC
Monomer impurity Dimer Impurity.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN201841037577 | 2018-10-04 | ||
| IN201841037577 | 2018-10-04 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2020070760A1 true WO2020070760A1 (en) | 2020-04-09 |
Family
ID=70054943
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/IN2019/050738 WO2020070760A1 (en) | 2018-10-04 | 2019-10-04 | An improved process for the preparation of 1,2,3-propanetriyl tris(4-phenylbutanoate) |
Country Status (1)
| Country | Link |
|---|---|
| WO (1) | WO2020070760A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113845420A (en) * | 2021-10-22 | 2021-12-28 | 安徽沃泰生物医药有限公司 | Synthesis process of phenylbutyric acid glyceride |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2607366A1 (en) * | 2011-12-21 | 2013-06-26 | Lunamed AG | Glycerol phenyl butyrate esters |
| WO2015063659A1 (en) * | 2013-10-30 | 2015-05-07 | Lupin Limited | Process for the preparation of glycerol phenylbutyrate |
-
2019
- 2019-10-04 WO PCT/IN2019/050738 patent/WO2020070760A1/en active Application Filing
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2607366A1 (en) * | 2011-12-21 | 2013-06-26 | Lunamed AG | Glycerol phenyl butyrate esters |
| WO2015063659A1 (en) * | 2013-10-30 | 2015-05-07 | Lupin Limited | Process for the preparation of glycerol phenylbutyrate |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113845420A (en) * | 2021-10-22 | 2021-12-28 | 安徽沃泰生物医药有限公司 | Synthesis process of phenylbutyric acid glyceride |
| CN113845420B (en) * | 2021-10-22 | 2024-04-16 | 安徽沃泰生物医药有限公司 | Synthesis process of phenylbutyrate |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| RU2483067C2 (en) | Methods and intermediate products for producing macrocyclic hepatitis c virus protease inhibitor | |
| KR102094928B1 (en) | Lysin-glutamic acid dipeptide derivatives | |
| JP5593342B2 (en) | Method for producing docetaxel | |
| AU2007226937A1 (en) | Docetaxel polymorphs and processes | |
| WO2020070760A1 (en) | An improved process for the preparation of 1,2,3-propanetriyl tris(4-phenylbutanoate) | |
| US20210163410A1 (en) | An improved process for the preparation of (2s)-2-[(4r)-2-oxo-4-propyltetrahydro-1h-pyrrol-1-yl] butanamide and its intermediates thereof | |
| JP3236282B1 (en) | How to purify pravastatin | |
| WO2020262259A1 (en) | Method for producing peptide compound, reagent for forming protective group, and fused polycyclic compound | |
| EP3464297A1 (en) | Process for preparation of eribulin and intermediates thereof | |
| US20210340156A1 (en) | Process for preparation of eribulin and intermediates thereof | |
| RU2326876C2 (en) | Method of paclitaxel preparation | |
| EP3986400B1 (en) | Processes and intermediates for producing diazaspiro lactam compounds | |
| EP2358693A2 (en) | Preparation of docetaxel | |
| EP3110791B1 (en) | Process for preparing 2,4-diamino-3-hydroxybutyric acid derivatives | |
| WO2016038622A2 (en) | Improved process for the preparation of [[2(s)-[[4(r)-(3-hydroxyphenyl)-3(r),4-dimethyl-1-piperidinyl]methyl]-1 -oxo-3-phenylpropyl]amino]acetic acid dihydrate | |
| JP5704763B2 (en) | Production of trans-4-aminocyclopent-2-ene-1-carboxylic acid derivative | |
| TWI565704B (en) | Processes and intermediates for preparing a macrocyclic protease inhibitor of hcv | |
| CN104558106B (en) | Preparation method of medicine for treating hepatitis C | |
| US20240124481A1 (en) | New compounds and methods of their manufacturing | |
| JP2010031004A (en) | New imidazole derivative, method for producing the same, and method for producing histidine amide derivative using the imidazole derivative | |
| KR100868116B1 (en) | Docetaxel·monopropyleneglycol clathrate and method for the preparation thereof | |
| Xu et al. | A Novel Method for the Synthesis of N-Per (poly) fluoroalkanesulfonyl Amino Acids | |
| JP5982720B2 (en) | Method for producing histidyl-prolinamide derivative using solid polymer support | |
| US20230174569A1 (en) | PROCESS PER PREPARING (3a,5a)-20-OXOPREGNAN-3-YL GLYCYL-L-VALINATE HYDROCHLORIDE | |
| RU2437875C2 (en) | Docetaxel polymorphs and synthesis methods thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| 121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 19869063 Country of ref document: EP Kind code of ref document: A1 |
|
| NENP | Non-entry into the national phase |
Ref country code: DE |
|
| 122 | Ep: pct application non-entry in european phase |
Ref document number: 19869063 Country of ref document: EP Kind code of ref document: A1 |